Process for the manufacture of delta4:6-3-oxo-19-hydroxy-steroids



United States Patent 3,211,762 PROCESS FOR THE MANUFACTURE 0F AOXO-H-HYDROXY-STERQIDS Albert Wettstein, Riehen, and Georg Anner, KarlHeusler,

Jaroslav Kalvoda, and Peter Wieland, Basel, Switzerland, assignors toCiha Corporation, New York, N.Y., a corporation of Delaware N0 Drawing.Filed Nov. 6, 1962, Ser. No. 235,850 Claims priority, applicationSwitzerland, Nov. 10, 1961, 13,092/61; Dec, 29, 1961, 15,176/61 7Claims. (Cl. 260--397.4)

The present invention provides a process for the manufacture of19-oxygenated A -3-oxosteroids of the androstane and pregnane series.These compounds are important intermediates for the manufacture ofcorresponding A -3-oxo-l9-nor compounds among which, for example, theknown A -3-oxo17a-ethiny1-1 7B-hydroxy-19-nor-androstadiene and itsderivatives methylated in position 6 and/or at the ethinyl group, areespecially valuable because of their strong progrestative action.Likewise, 6- dehydro-19-norprogesterone and more especially6-dehydro-17a-acetoxy-19-norprogesterone are much more active than theprogesterones occurring in nature.

Two processes are known for the manufacture of A 3-oxosteroids from thecorresponding A -3-oxosteroids, namely bromination in position 6 withN-brornosuccinimide followed by dehydrobromination with the aid of abase such as collidine or the like, and the industrially moreinteresting introduction of the new double bond in one stage. The latterreaction can be carried out in the case of 19-unsubstituted steroids bytreatment with manganese dioxide or with a quinone in an inert solvent.Although these processes can also be applied to 19-norsteroids, the

yields obtained are so low that said processes have not been adoptedindustrially. On treatment of Not-methyl- 19-nortestosterone Withchloranil in boiling tertiary butanol, for example, there are obtainedonly traces of the corresponding 6-dehydro compound. Since theconversion of the readily accessible A -3-oxosteroids into thecorresponding 19-nor compounds has not been achieved to date, anindustrially more advantageous process for the manufacture of saidsteroids is of considerable importance.

The present invention is based on the observation that A-3-oxo-19-norsteroids can be manufactured in good yields by converting19-oxygenated A -3-oxo-steroids into l9-oxygenated A -3-oxosteroids andsplitting off the angular (3-19 group, if desired after having oxidizeda l9-hydroxyl group.

The present invention provides more especially a process for themanufacture of 19-oxygenated A -3-oxosteroids from 19-oxygenated A-3-oxosteroids, wherein in known manner a double bond is introduced inposition 6:7 in a 19-oxygenated A -3-oxosteroid by treatment with adehydrogenating agent.

Suitable dehydrogenating agents are, for example, manganese dioxide, andmore especially quinones, for example benzoquinone, chloranil,dicyano-dichloro-benzoquinones, 2 o-dichloro-benzoquinone, 1:4-naphthoquinone, paratoluquinone and the like. The reaction is carriedout in an inert solvent at an elevated temperature, preferably rangingfrom 70 to 180 C. Suitable solvents are, for example, aromatichydrocarbons such as toluene, xylene, c'hlorobenzene,para-dichlorobenzene, alcohols such as tertiary butanol, secondary amylalcohol, tertiary amyl alcohol, or esters such as methyl butyrate, butylacetate, propyl propionate and the like, or also lower aliphaticcarboxylic acids such as acetic, propionic, butyric acid or the like.

Starting materials suitable for use in the present process are19-oxygenated A -3-oxosteroids of the androstane,

pregnane, cholane, cholestane, spirostane and cardanolide series whosering system contains more especially in one or several of the positions1, 2, 6, 8, 3, 11, 12, 14, 15, 16, 17, 20, 21 further substituents, suchas free or functionally converted oxo groups, or esterified oretherified hydroxyl groups, or alkyl (for example methyl) groups and/ orhalogen atoms. The term converted oxo groups refers both to ketalizedoxo groups and to oxo groups converted into enol derivatives, forexample enolethers or enolcsters. Furthermore, the starting materialsmay contain additional double bonds, for example in position 16:17 or inthe side chain.

The 19-oxygenated A -3-oxo compounds to be used as starting materialsare, above all, compounds containing a free, esterified or etherified19-hydroxyl group, or a free or protected 19-oxo group or an esterifiedsteroid-19-acid. A -3-oxo-19-hydroxysteroids are readily accessible from19-unsubstituted steroids by microbiological hydroxylation or accordingto the process of US. patent application Ser. No. 122,656, filed July10, 1961 now U.S. Patent 3,077,482, by Albert Wettstein et a1. Thesecompounds can be esterified or etherified in position 19 in knownmanner. Alternatively, the 19-hydroxy compounds can be oxidized to19-oxo compounds and 19-acids as described in said application.

Particularly valuable starting materials are those 19- oxygenated A-3-oxosteroids which contain in position 6 a methyl group or preferablya halogen atom, for example a chlorine or fluorine atom. The halogenatedderivatives can be prepared from a 4-unsubstituted A -3-ketone by firstconverting it into an enol derivative (for example into an enolester oran enolacetate, accompanied by acylation of a 19-hydroxy1 grouppresent), for example by treatment with isopropenyl acetate in thepresence of an acidic catalyst, for example sulfuric or toluene sulfonicacid, or it may be converted into an enolether by treatment with anortho-ester, for example orthoformic acid methyl or ethyl ester, withaddition of an acidic catalyst. These enol derivatives are thenhalogenated in known manner with a halogenating agent such asN-chlorosuccinimide, N-chl-oroacetamide, or perchloryl fluoride, toyield the A -3-oxo-6-halogeno compounds.

As specific starting materials there may be mentioned, for example: A -317dioxo-19-hydroxyandrostene, A -3-oxo-17/3: 19-dihydroxyandrostene, A-3-oxo-17a-methyl-17B: 19-dihydroxyandrostene, A -3-oxo-17a-ethyl-17 3:l9-dihydroxyandrostene, A -3-0xo-17wallyl-17B: 19-dihydroxyandrostene, A-3-oxo-17u-vinyl-17 3: 19 -dihydroxyandrostene, A-3-oxo-17u-ethinyl-17/3: 19-dihydroxyandrostene, A -3-oxo17a-(2-methyl-ethinyl) -17,8 19-dihydroxyandrostene and their esters, moreespecially the monoesters and diesters, for example the formates,acetates, trifiuoroacetates, propionates and benzoates.

Furthermore, there may be mentioned:

A -3 20-dioxo-19-hydroxypregnene,

A -3 20-dioxo-17a: 19-dihydroxypregnene,

A -3 :20-dioxo-17a-acetoxy-19-hydroxypregnene,

A -3 20-dioxo-17u-caproyloxy-19-hydroxypregnene,

A -3 20-dioxo-6a-chloro-19-hydroxy-17m-acetoxy and17a-caproyloxypregnene, and the corresponding 19-esters, for exampleformates, acetates, propionates, trifiuoro acetates and benzoates.

Another object of the invention are 19-oxygenated A-3-oxo-6-halogeno-19-hydroxypregnadienes, more especially:

A -3:2O-di0xo-6-chloro-, 6-b1'omoand -6-fluoro-19- hydroxypregnadiene, A-3 :20-dioxo-6-chloro-, -6-bromoand6-fluoro-17:x:19-dihydroxypregnadiene and their esters, such asacetates, propionates, caproates and undecylenates.

Taking into consideration the ease with which the 19- carbon atom of19-oxygenated A -3-ketones is split off with formation of19-norsteroids, it is surprising that the dehydrogenation of theinvention gives such a good yield comparable with the yield obtainedwith 19-unsubstituted A 3-ketones. It is especially unexpected that evencompounds containing a free 19-hydroxyl group can be used.

The conversion of the A -3-oxo-19-hydroxysteroids into A-3-oxo-19-norsteroids by the present process has been described indetail in U.S. patent application Ser. No. 208,634, filed July 9, 1962by Albert Wettstein et al. according to that process A-3-oxo-19-hydroxysteroiddienes are oxidized to steroid-19-acids whichare then decarboxylated.

The following examples illustrate the process of the invention.

Example 1 A solution of 8.0 grams of A -3:17-dioxo-19-hydroxyandrostenein 500 cc. of tertiary butanol is mixed with 28.0 grams of chloranil andthe whole is refluxed for 3 hours. The reaction mixture is cooled, theexcess chloranil is filtered off, and the filtrate is evaporated undervacuum. The residue is dissolved in a 4:1-mixture of ether and methylenechloride, and the solution is washed with ice-cold sodium hydroxidesolution of strength and then with water, dried and evaporated undervacuum. One recrystallization from methylene chloride-i-petroleum etheryields 5.45 grams of slightly yellowish A3:17-dioxo-19-hydroxyandrostene melting at 198200 C. Optical rotation[a] =+135.6 (c.=0.813). Ultraviolet spectrum: k 283 m (e=25 400).

The infra-red spectrum of the compound contains absorption bands, interalia, at 2.75, 5.75, 6.01, 6.16, 6.29, 7.36, 820, 8.27, 9.48 and 11.38

Example 2 A mixture of 100 mg. of A -3:20-dioxo-17a-acetoxy-19-hydroxypregnene, 350 mg. of chloranil and cc. of tertiary butanol isrefluxed for 1 /2 hours. The reaction mixture is cooled, freed fromexcess chloranil by filtration, and the yellow solution is evaporatedunder vacuum. The residue is taken up in a 4:1-mixture of ether andmethylene chloride and the extract is successively washed with ice-coldN-sodium hydroxide solution and water, dried and evaporated. Bytriturating the crude product with ether there are obtained 71 mg. of A-3:20-dioxo- 17e-acetoxy-19-hydroxypregnadiene which is purified byrecrystallization from methylene chloride+ether+petroleum ether; itmelts at 200201 C. Ultra-violet absorption A 284 m (e=22 400). Infra-redabsorption bands, inter alia, at 2.82, 5.77, 5.80, 6.02, 6.19, 6.32,9.00 and 11.35,u..

Example 3 A suspension of 1.50 grams of A -3 :20-di0xo-6a-chloro-17e-acetoxy-19-hydroxypregnene and 4.0 grams of 2:3dichloro-5:6-dicyanobenzoquinone in 100 cc. of tertiary butanol is stirred underreflux for 2 hours, then allowed to cool, and the dark-colored solutionis filtered off from the excess quinone. The filtrate is evaporatedunder vacuum and the residue is extracted with ether-i-methylenechloride (4:1), and the extract is exhaustively washed with N-sodiumhydroxide solution and water, dried, and evaporated under vacuum. Thereddish brown crude product is dissolved in cc. of benzene andchromatographed on 30 times its own weight of neutral alumina (activityII). Mixtures of benzene and ethyl acetate elute 1.01 grams of pure A-3:20-dioxo-6-chloro-17a-acetoxy-19- hydroxypregnadiene. Its infra-redspectrum contains absorption bands, inter alia, at 2.82, 5.76, 5.82,6.03, 6.22, 6.31, 8.10 and 11.30,u.. Ultra-violet maximum at 283 m (6 23500).

The A -3 20-dioxo-6e-chloro-17a-acetoxy-19-hydroxypregnene used asstarting material can be prepared by the known methods referred to abovefrom A -3 :20-dioxo- 17u-acetoxy-19-hydroxypregnene melting at 233 C.The altter product-after acetylating the 19-hydroxyl group to form thel7azl9-diacetate (melting at 208-209" C.)is converted in a solution indioxane with orthoformic acid ethyl ester and sulfuric acid as catalystinto the corresponding enolether which does not crystallize (infra-redabsorption bands, inter alia, at 5.78, 6.05, 6.15, 8.15, 8.41, 8.53,10.37 and 11.62,!1.) and, on treatment with N-chlorosuccinimide inacetone, furnishes crude A-3Z20-dl0XO-6onchloro-17a:19-diacetoxypregnene in which the 19-acetoxygroup can be selectively hydrolyzed with sodium bicarbonate.

What is claimed is:

1. A -3 :20-dioxo-6-halogen-19-hydroxy-pregnadiene.

2. A -3 20-dioxo-6-chloro-19-hydroxy-pregnadiene.

3. A 3:20 dioxo 6 halogen 17:19 dihydroxypregnadiene.

4. A member selected from the group consisting of a 17,19-diester of thecompound claimed in claim 3 derived from a carboxylic acid having atmost 15 carbon atoms.

5. A 3:20 dioxo 6 chloro 171x219 dihydroxypregnadiene.

6. A member selected from the group consisting of a 17,19-diester of thecompound claimed in claim 5 derived from a carboxylic acid having atmost 15 carbon atoms.

7. A 3:20 dioxo 6 chloro 17a acetoxy 19- hydroxypregnadiene.

References Cited by the Examiner UNITED STATES PATENTS 3,040,038 6/62Shull 260-23955 3,076,823 2/63 Ringold et al 260397.4 3,087,940 4/63Rubin 260397.4

OTHER REFERENCES Westerhof, et al.: Rec. Trav. Chim., vol. 79, (1960),pp. 794-799.

LEWIS GOTTS, Primary Examiner.

1. $4:6-3:20-DIOXO-6-HALOGEN-19- HYDROXY-PREGNADIENE.